CA2674154A1 - Derives azaspiro - Google Patents
Derives azaspiro Download PDFInfo
- Publication number
- CA2674154A1 CA2674154A1 CA002674154A CA2674154A CA2674154A1 CA 2674154 A1 CA2674154 A1 CA 2674154A1 CA 002674154 A CA002674154 A CA 002674154A CA 2674154 A CA2674154 A CA 2674154A CA 2674154 A1 CA2674154 A1 CA 2674154A1
- Authority
- CA
- Canada
- Prior art keywords
- alkyl
- formula
- furo
- spiro
- pyridine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 150000001875 compounds Chemical class 0.000 claims abstract description 155
- -1 their manufacture Substances 0.000 claims abstract description 62
- 229910052720 vanadium Inorganic materials 0.000 claims abstract description 43
- 208000019901 Anxiety disease Diseases 0.000 claims abstract description 11
- 230000036506 anxiety Effects 0.000 claims abstract description 11
- 208000020401 Depressive disease Diseases 0.000 claims abstract description 10
- 239000003814 drug Substances 0.000 claims abstract description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 7
- 230000002265 prevention Effects 0.000 claims abstract description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 98
- 239000001257 hydrogen Substances 0.000 claims description 88
- 229910052739 hydrogen Inorganic materials 0.000 claims description 88
- 229910052757 nitrogen Inorganic materials 0.000 claims description 84
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 72
- 229910052760 oxygen Inorganic materials 0.000 claims description 64
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 62
- 125000005843 halogen group Chemical group 0.000 claims description 54
- 238000000034 method Methods 0.000 claims description 49
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 43
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 39
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 39
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 38
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 38
- 229910052727 yttrium Inorganic materials 0.000 claims description 29
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 26
- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 claims description 24
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 24
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 23
- 125000005842 heteroatom Chemical group 0.000 claims description 23
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 20
- 125000000623 heterocyclic group Chemical group 0.000 claims description 19
- 229960003726 vasopressin Drugs 0.000 claims description 19
- 125000006642 (C1-C6) cyanoalkyl group Chemical group 0.000 claims description 18
- 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 claims description 18
- GXBMIBRIOWHPDT-UHFFFAOYSA-N Vasopressin Natural products N1C(=O)C(CC=2C=C(O)C=CC=2)NC(=O)C(N)CSSCC(C(=O)N2C(CCC2)C(=O)NC(CCCN=C(N)N)C(=O)NCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(CCC(N)=O)NC(=O)C1CC1=CC=CC=C1 GXBMIBRIOWHPDT-UHFFFAOYSA-N 0.000 claims description 18
- 108010004977 Vasopressins Proteins 0.000 claims description 18
- 102000002852 Vasopressins Human genes 0.000 claims description 18
- KBZOIRJILGZLEJ-LGYYRGKSSA-N argipressin Chemical compound C([C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@@H](C(N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N1)=O)N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)NCC(N)=O)C1=CC=CC=C1 KBZOIRJILGZLEJ-LGYYRGKSSA-N 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 13
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 11
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 11
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 11
- 238000002360 preparation method Methods 0.000 claims description 10
- 206010007558 Cardiac failure chronic Diseases 0.000 claims description 7
- 208000005171 Dysmenorrhea Diseases 0.000 claims description 7
- 206010013935 Dysmenorrhoea Diseases 0.000 claims description 7
- 206010020772 Hypertension Diseases 0.000 claims description 7
- 206010029164 Nephrotic syndrome Diseases 0.000 claims description 7
- 208000021384 Obsessive-Compulsive disease Diseases 0.000 claims description 7
- 208000019425 cirrhosis of liver Diseases 0.000 claims description 7
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 150000002367 halogens Chemical class 0.000 claims description 7
- 230000028327 secretion Effects 0.000 claims description 7
- HHVFLYPJVPQIOB-NTEVMMBTSA-N [6-chloro-1-[[(2s)-pyrrolidin-2-yl]methyl]indol-3-yl]-spiro[7h-furo[3,4-b]pyridine-5,4'-piperidine]-1'-ylmethanone;dihydrochloride Chemical compound Cl.Cl.C12=CC(Cl)=CC=C2C(C(=O)N2CCC3(CC2)C2=CC=CN=C2CO3)=CN1C[C@@H]1CCCN1 HHVFLYPJVPQIOB-NTEVMMBTSA-N 0.000 claims description 5
- LVSLYONFEDZZAL-NRFANRHFSA-N tert-butyl (2s)-2-[[6-chloro-3-(spiro[7h-furo[3,4-b]pyridine-5,4'-piperidine]-1'-carbonyl)indol-1-yl]methyl]pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC[C@H]1CN1C2=CC(Cl)=CC=C2C(C(=O)N2CCC3(CC2)C2=CC=CN=C2CO3)=C1 LVSLYONFEDZZAL-NRFANRHFSA-N 0.000 claims description 5
- XAPWTKOWWWWGEK-IBGZPJMESA-N [6-chloro-1-[[(2s)-1-methylpyrrolidin-2-yl]methyl]indol-3-yl]-spiro[7h-furo[3,4-b]pyridine-5,4'-piperidine]-1'-ylmethanone Chemical compound CN1CCC[C@H]1CN1C2=CC(Cl)=CC=C2C(C(=O)N2CCC3(CC2)C2=CC=CN=C2CO3)=C1 XAPWTKOWWWWGEK-IBGZPJMESA-N 0.000 claims description 4
- 125000001041 indolyl group Chemical group 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- JSAGCZKQSXRQHV-FQEVSTJZSA-N [6-chloro-1-[[(2s)-1-methylpyrrolidin-2-yl]methyl]indol-3-yl]-spiro[1h-furo[3,4-c]pyridine-3,4'-piperidine]-1'-ylmethanone Chemical compound CN1CCC[C@H]1CN1C2=CC(Cl)=CC=C2C(C(=O)N2CCC3(CC2)C2=CN=CC=C2CO3)=C1 JSAGCZKQSXRQHV-FQEVSTJZSA-N 0.000 claims description 3
- LBWNOSLCWQUTSF-FQEVSTJZSA-N [6-chloro-1-[[(2s)-1-methylpyrrolidin-2-yl]methyl]indol-3-yl]-spiro[5h-furo[3,4-b]pyridine-7,4'-piperidine]-1'-ylmethanone Chemical compound CN1CCC[C@H]1CN1C2=CC(Cl)=CC=C2C(C(=O)N2CCC3(CC2)C2=NC=CC=C2CO3)=C1 LBWNOSLCWQUTSF-FQEVSTJZSA-N 0.000 claims description 3
- FTNGTGTZEWCHND-TXEPZDRESA-N [6-chloro-1-[[(2s)-pyrrolidin-2-yl]methyl]indol-3-yl]-spiro[1h-furo[3,4-c]pyridine-3,4'-piperidine]-1'-ylmethanone;dihydrochloride Chemical compound Cl.Cl.C12=CC(Cl)=CC=C2C(C(=O)N2CCC3(CC2)C2=CN=CC=C2CO3)=CN1C[C@@H]1CCCN1 FTNGTGTZEWCHND-TXEPZDRESA-N 0.000 claims description 3
- IZAHRWBFQLEZJL-TXEPZDRESA-N [6-chloro-1-[[(2s)-pyrrolidin-2-yl]methyl]indol-3-yl]-spiro[5h-furo[3,4-b]pyridine-7,4'-piperidine]-1'-ylmethanone;dihydrochloride Chemical compound Cl.Cl.C12=CC(Cl)=CC=C2C(C(=O)N2CCC3(CC2)C2=NC=CC=C2CO3)=CN1C[C@@H]1CCCN1 IZAHRWBFQLEZJL-TXEPZDRESA-N 0.000 claims description 3
- RMKRYUKAFCDHJF-UHFFFAOYSA-N (6-chloro-1h-indol-3-yl)-spiro[1h-furo[3,4-c]pyridine-3,4'-piperidine]-1'-ylmethanone Chemical compound O1CC2=CC=NC=C2C1(CC1)CCN1C(=O)C1=CNC2=CC(Cl)=CC=C21 RMKRYUKAFCDHJF-UHFFFAOYSA-N 0.000 claims description 2
- LWINSKSAAQRWTC-UHFFFAOYSA-N (6-chloro-1h-indol-3-yl)-spiro[5h-furo[3,4-b]pyridine-7,4'-piperidine]-1'-ylmethanone Chemical compound O1CC2=CC=CN=C2C1(CC1)CCN1C(=O)C1=CNC2=CC(Cl)=CC=C21 LWINSKSAAQRWTC-UHFFFAOYSA-N 0.000 claims description 2
- IPIIGNYKOUWWDJ-UHFFFAOYSA-N (6-chloro-1h-indol-3-yl)-spiro[7h-furo[3,4-b]pyridine-5,4'-piperidine]-1'-ylmethanone Chemical compound O1CC2=NC=CC=C2C1(CC1)CCN1C(=O)C1=CNC2=CC(Cl)=CC=C21 IPIIGNYKOUWWDJ-UHFFFAOYSA-N 0.000 claims description 2
- KHIBXLZGSPJOEN-UHFFFAOYSA-N [6-chloro-1-[(3,5-difluorophenyl)methyl]indol-3-yl]-spiro[5h-furo[3,4-b]pyridine-7,4'-piperidine]-1'-ylmethanone Chemical compound FC1=CC(F)=CC(CN2C3=CC(Cl)=CC=C3C(C(=O)N3CCC4(CC3)C3=NC=CC=C3CO4)=C2)=C1 KHIBXLZGSPJOEN-UHFFFAOYSA-N 0.000 claims description 2
- XBGMMIDCMVKBKG-UHFFFAOYSA-N [6-chloro-1-[(3,5-difluorophenyl)methyl]indol-3-yl]-spiro[7h-furo[3,4-b]pyridine-5,4'-piperidine]-1'-ylmethanone Chemical compound FC1=CC(F)=CC(CN2C3=CC(Cl)=CC=C3C(C(=O)N3CCC4(CC3)C3=CC=CN=C3CO4)=C2)=C1 XBGMMIDCMVKBKG-UHFFFAOYSA-N 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- BPBMARQWXNTSBS-QFIPXVFZSA-N tert-butyl (2s)-2-[[6-chloro-3-(spiro[1h-furo[3,4-c]pyridine-3,4'-piperidine]-1'-carbonyl)indol-1-yl]methyl]pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC[C@H]1CN1C2=CC(Cl)=CC=C2C(C(=O)N2CCC3(CC2)C2=CN=CC=C2CO3)=C1 BPBMARQWXNTSBS-QFIPXVFZSA-N 0.000 claims description 2
- INZIZYWDRVHGNO-QFIPXVFZSA-N tert-butyl (2s)-2-[[6-chloro-3-(spiro[5h-furo[3,4-b]pyridine-7,4'-piperidine]-1'-carbonyl)indol-1-yl]methyl]pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC[C@H]1CN1C2=CC(Cl)=CC=C2C(C(=O)N2CCC3(CC2)C2=NC=CC=C2CO3)=C1 INZIZYWDRVHGNO-QFIPXVFZSA-N 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 11
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 claims 1
- 239000012039 electrophile Substances 0.000 claims 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 229940044551 receptor antagonist Drugs 0.000 abstract description 3
- 239000002464 receptor antagonist Substances 0.000 abstract description 3
- 201000010099 disease Diseases 0.000 abstract description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 53
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 51
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 42
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 33
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 32
- 239000007787 solid Substances 0.000 description 32
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 29
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 25
- 239000011541 reaction mixture Substances 0.000 description 24
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- 239000000203 mixture Substances 0.000 description 20
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 19
- 229910052938 sodium sulfate Inorganic materials 0.000 description 19
- 235000011152 sodium sulphate Nutrition 0.000 description 19
- 239000012044 organic layer Substances 0.000 description 17
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 16
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 14
- 239000002253 acid Substances 0.000 description 14
- 150000001408 amides Chemical class 0.000 description 14
- 238000003818 flash chromatography Methods 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- 108010041332 Very Late Antigen Receptors Proteins 0.000 description 12
- 239000000460 chlorine Substances 0.000 description 11
- 238000010168 coupling process Methods 0.000 description 11
- 238000005859 coupling reaction Methods 0.000 description 11
- 239000010410 layer Substances 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 10
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 10
- 150000001412 amines Chemical class 0.000 description 10
- 230000008878 coupling Effects 0.000 description 10
- 125000002541 furyl group Chemical group 0.000 description 10
- 125000004076 pyridyl group Chemical group 0.000 description 10
- 238000010992 reflux Methods 0.000 description 10
- 125000001544 thienyl group Chemical group 0.000 description 10
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 10
- 229910052721 tungsten Inorganic materials 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical class O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- KMAKOBLIOCQGJP-UHFFFAOYSA-N indole-3-carboxylic acid Chemical compound C1=CC=C2C(C(=O)O)=CNC2=C1 KMAKOBLIOCQGJP-UHFFFAOYSA-N 0.000 description 9
- 239000002775 capsule Substances 0.000 description 8
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 8
- 229910052801 chlorine Inorganic materials 0.000 description 8
- 229910052731 fluorine Inorganic materials 0.000 description 8
- 125000002883 imidazolyl group Chemical group 0.000 description 8
- 125000000842 isoxazolyl group Chemical group 0.000 description 8
- 125000002971 oxazolyl group Chemical group 0.000 description 8
- 125000003226 pyrazolyl group Chemical group 0.000 description 8
- 125000000714 pyrimidinyl group Chemical group 0.000 description 8
- 229920006395 saturated elastomer Polymers 0.000 description 8
- 125000001424 substituent group Chemical group 0.000 description 8
- 125000000335 thiazolyl group Chemical group 0.000 description 8
- 125000000217 alkyl group Chemical group 0.000 description 7
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- 125000002757 morpholinyl group Chemical group 0.000 description 7
- 125000003386 piperidinyl group Chemical group 0.000 description 7
- 229910052702 rhenium Inorganic materials 0.000 description 7
- 229910052703 rhodium Inorganic materials 0.000 description 7
- 229910000104 sodium hydride Inorganic materials 0.000 description 7
- 239000000829 suppository Substances 0.000 description 7
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- 239000000546 pharmaceutical excipient Substances 0.000 description 6
- 125000003373 pyrazinyl group Chemical group 0.000 description 6
- 125000002098 pyridazinyl group Chemical group 0.000 description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
- 239000001828 Gelatine Substances 0.000 description 5
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 5
- 239000013543 active substance Substances 0.000 description 5
- 210000004556 brain Anatomy 0.000 description 5
- 239000012267 brine Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 125000001153 fluoro group Chemical group F* 0.000 description 5
- 229920000159 gelatin Polymers 0.000 description 5
- 235000019322 gelatine Nutrition 0.000 description 5
- 125000001786 isothiazolyl group Chemical group 0.000 description 5
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 description 5
- 125000003566 oxetanyl group Chemical group 0.000 description 5
- 125000000466 oxiranyl group Chemical group 0.000 description 5
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 5
- 125000000168 pyrrolyl group Chemical group 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 5
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 4
- DOCNWGLGOYLWRC-UHFFFAOYSA-N 1-(6-chloro-1h-indol-3-yl)-2,2,2-trifluoroethanone Chemical compound ClC1=CC=C2C(C(=O)C(F)(F)F)=CNC2=C1 DOCNWGLGOYLWRC-UHFFFAOYSA-N 0.000 description 4
- SJZKULRDWHPHGG-UHFFFAOYSA-N 1-benzylpiperidin-4-one Chemical compound C1CC(=O)CCN1CC1=CC=CC=C1 SJZKULRDWHPHGG-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 229920002261 Corn starch Polymers 0.000 description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- 125000003545 alkoxy group Chemical group 0.000 description 4
- 150000008064 anhydrides Chemical class 0.000 description 4
- 125000002393 azetidinyl group Chemical group 0.000 description 4
- 125000004069 aziridinyl group Chemical group 0.000 description 4
- 230000027455 binding Effects 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000008120 corn starch Substances 0.000 description 4
- GUVUOGQBMYCBQP-UHFFFAOYSA-N dmpu Chemical compound CN1CCCN(C)C1=O GUVUOGQBMYCBQP-UHFFFAOYSA-N 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 125000002632 imidazolidinyl group Chemical group 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 125000004628 isothiazolidinyl group Chemical group S1N(CCC1)* 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- 235000019198 oils Nutrition 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- 229910052763 palladium Inorganic materials 0.000 description 4
- 229920005862 polyol Polymers 0.000 description 4
- 150000003077 polyols Chemical class 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 4
- FMACSIUGOAYKJC-UHFFFAOYSA-N spiro[7h-furo[3,4-b]pyridine-5,4'-piperidine] Chemical compound C12=CC=CN=C2COC21CCNCC2 FMACSIUGOAYKJC-UHFFFAOYSA-N 0.000 description 4
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 4
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 4
- 125000003507 tetrahydrothiofenyl group Chemical group 0.000 description 4
- 125000001984 thiazolidinyl group Chemical group 0.000 description 4
- 125000001730 thiiranyl group Chemical group 0.000 description 4
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 4
- PKHVSZSOEPTKFB-ZDUSSCGKSA-N 6-chloro-1-[[(2s)-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidin-2-yl]methyl]indole-3-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CCC[C@H]1CN1C2=CC(Cl)=CC=C2C(C(O)=O)=C1 PKHVSZSOEPTKFB-ZDUSSCGKSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 3
- 239000004215 Carbon black (E152) Substances 0.000 description 3
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 102000004136 Vasopressin Receptors Human genes 0.000 description 3
- 108090000643 Vasopressin Receptors Proteins 0.000 description 3
- 210000004727 amygdala Anatomy 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 229910002091 carbon monoxide Inorganic materials 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 125000001309 chloro group Chemical group Cl* 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000012230 colorless oil Substances 0.000 description 3
- 239000008298 dragée Substances 0.000 description 3
- 229930195733 hydrocarbon Natural products 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 3
- 239000000825 pharmaceutical preparation Substances 0.000 description 3
- 238000002953 preparative HPLC Methods 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 238000010791 quenching Methods 0.000 description 3
- 230000000171 quenching effect Effects 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- AYJYOTMPNCIHOG-UHFFFAOYSA-N spiro[1h-furo[3,4-c]pyridine-3,4'-piperidine] Chemical compound C12=CN=CC=C2COC21CCNCC2 AYJYOTMPNCIHOG-UHFFFAOYSA-N 0.000 description 3
- BVROHWVEAHLAOW-UHFFFAOYSA-N spiro[5h-furo[3,4-b]pyridine-7,4'-piperidine] Chemical compound C12=NC=CC=C2COC21CCNCC2 BVROHWVEAHLAOW-UHFFFAOYSA-N 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- 239000001993 wax Substances 0.000 description 3
- QIQZUABMLGJKJP-UHFFFAOYSA-N (2-bromopyridin-3-yl)methanol Chemical compound OCC1=CC=CN=C1Br QIQZUABMLGJKJP-UHFFFAOYSA-N 0.000 description 2
- LQBUZBOVEZBDEB-UHFFFAOYSA-N (3-bromopyridin-4-yl)methanol Chemical compound OCC1=CC=NC=C1Br LQBUZBOVEZBDEB-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- IYKRSBWKJJLFDT-UHFFFAOYSA-N 6-chloro-1-[(3,5-difluorophenyl)methyl]indole-3-carboxylic acid Chemical compound C12=CC(Cl)=CC=C2C(C(=O)O)=CN1CC1=CC(F)=CC(F)=C1 IYKRSBWKJJLFDT-UHFFFAOYSA-N 0.000 description 2
- WHQHEMBHJZAHSB-UHFFFAOYSA-N 6-chloro-1h-indole-3-carboxylic acid Chemical compound ClC1=CC=C2C(C(=O)O)=CNC2=C1 WHQHEMBHJZAHSB-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 description 2
- SORMTKLBNQJHHZ-SFHVURJKSA-N [6-chloro-1-[[(2s)-pyrrolidin-2-yl]methyl]indol-3-yl]-spiro[7h-furo[3,4-b]pyridine-5,4'-piperidine]-1'-ylmethanone Chemical compound C12=CC(Cl)=CC=C2C(C(=O)N2CCC3(CC2)C2=CC=CN=C2CO3)=CN1C[C@@H]1CCCN1 SORMTKLBNQJHHZ-SFHVURJKSA-N 0.000 description 2
- 125000003342 alkenyl group Chemical group 0.000 description 2
- 239000005557 antagonist Substances 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 239000011324 bead Substances 0.000 description 2
- 230000006399 behavior Effects 0.000 description 2
- 239000012148 binding buffer Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 230000002526 effect on cardiovascular system Effects 0.000 description 2
- 239000012834 electrophilic reactant Substances 0.000 description 2
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 2
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 description 2
- 239000013604 expression vector Substances 0.000 description 2
- 239000003925 fat Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 125000001072 heteroaryl group Chemical group 0.000 description 2
- 150000002430 hydrocarbons Chemical group 0.000 description 2
- 150000002475 indoles Chemical class 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 238000011813 knockout mouse model Methods 0.000 description 2
- 125000005647 linker group Chemical group 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 239000012139 lysis buffer Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 210000002464 muscle smooth vascular Anatomy 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 230000009871 nonspecific binding Effects 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 229960004793 sucrose Drugs 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- CIWDWHXBAWTUES-UHFFFAOYSA-N (1'-benzylspiro[7h-furo[3,4-b]pyridine-5,4'-piperidine]-7-yl) acetate Chemical compound C12=CC=CN=C2C(OC(=O)C)OC1(CC1)CCN1CC1=CC=CC=C1 CIWDWHXBAWTUES-UHFFFAOYSA-N 0.000 description 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- NOMJCWNXRGLWDJ-UHFFFAOYSA-N 1'-benzylspiro[1h-furo[3,4-c]pyridine-3,4'-piperidine] Chemical compound C1CC2(C3=CN=CC=C3CO2)CCN1CC1=CC=CC=C1 NOMJCWNXRGLWDJ-UHFFFAOYSA-N 0.000 description 1
- GVLFXYZCHLAVCX-UHFFFAOYSA-N 1'-benzylspiro[5h-furo[3,4-b]pyridine-7,4'-piperidine] Chemical compound C1CC2(C3=NC=CC=C3CO2)CCN1CC1=CC=CC=C1 GVLFXYZCHLAVCX-UHFFFAOYSA-N 0.000 description 1
- DRWQMNAGVDRWMJ-UHFFFAOYSA-N 1'-benzylspiro[7h-furo[3,4-b]pyridine-5,4'-piperidine] Chemical compound C1CC2(C3=CC=CN=C3CO2)CCN1CC1=CC=CC=C1 DRWQMNAGVDRWMJ-UHFFFAOYSA-N 0.000 description 1
- XBGIPVIEDQGJFM-UHFFFAOYSA-N 1'-benzylspiro[furo[3,4-b]pyridine-5,4'-piperidine]-7-one Chemical compound C12=CC=CN=C2C(=O)OC1(CC1)CCN1CC1=CC=CC=C1 XBGIPVIEDQGJFM-UHFFFAOYSA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- KVSVNRFSKRFPIL-UHFFFAOYSA-N 1-(bromomethyl)-3,5-difluorobenzene Chemical compound FC1=CC(F)=CC(CBr)=C1 KVSVNRFSKRFPIL-UHFFFAOYSA-N 0.000 description 1
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 1
- HMUNWXXNJPVALC-UHFFFAOYSA-N 1-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C(CN1CC2=C(CC1)NN=N2)=O HMUNWXXNJPVALC-UHFFFAOYSA-N 0.000 description 1
- LJSNQAWPDIIZCF-UHFFFAOYSA-N 1-[6-chloro-1-[(3,5-difluorophenyl)methyl]indol-3-yl]-2,2,2-trifluoroethanone Chemical compound FC1=CC(F)=CC(CN2C3=CC(Cl)=CC=C3C(C(=O)C(F)(F)F)=C2)=C1 LJSNQAWPDIIZCF-UHFFFAOYSA-N 0.000 description 1
- SFKRLRKKCKEWBH-UHFFFAOYSA-N 1-benzyl-4-(2-bromopyridin-3-yl)piperidin-4-ol Chemical compound C1CC(O)(C=2C(=NC=CC=2)Br)CCN1CC1=CC=CC=C1 SFKRLRKKCKEWBH-UHFFFAOYSA-N 0.000 description 1
- GEJFIODWTXDWKQ-UHFFFAOYSA-N 1-benzyl-4-[3-(hydroxymethyl)pyridin-2-yl]piperidin-4-ol Chemical compound OCC1=CC=CN=C1C1(O)CCN(CC=2C=CC=CC=2)CC1 GEJFIODWTXDWKQ-UHFFFAOYSA-N 0.000 description 1
- KHYWGLHSDVZGKW-UHFFFAOYSA-N 1-benzyl-4-[4-(hydroxymethyl)pyridin-3-yl]piperidin-4-ol Chemical compound OCC1=CC=NC=C1C1(O)CCN(CC=2C=CC=CC=2)CC1 KHYWGLHSDVZGKW-UHFFFAOYSA-N 0.000 description 1
- SLMHHOVQRSSRCV-UHFFFAOYSA-N 2,3-dibromopyridine Chemical compound BrC1=CC=CN=C1Br SLMHHOVQRSSRCV-UHFFFAOYSA-N 0.000 description 1
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- XXZCIYUJYUESMD-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-3-(morpholin-4-ylmethyl)pyrazol-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C=1C(=NN(C=1)CC(=O)N1CC2=C(CC1)NN=N2)CN1CCOCC1 XXZCIYUJYUESMD-UHFFFAOYSA-N 0.000 description 1
- WWSJZGAPAVMETJ-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-3-ethoxypyrazol-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C=1C(=NN(C=1)CC(=O)N1CC2=C(CC1)NN=N2)OCC WWSJZGAPAVMETJ-UHFFFAOYSA-N 0.000 description 1
- WZFUQSJFWNHZHM-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)CC(=O)N1CC2=C(CC1)NN=N2 WZFUQSJFWNHZHM-UHFFFAOYSA-N 0.000 description 1
- ZRPAUEVGEGEPFQ-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]pyrazol-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C=1C=NN(C=1)CC(=O)N1CC2=C(CC1)NN=N2 ZRPAUEVGEGEPFQ-UHFFFAOYSA-N 0.000 description 1
- YJLUBHOZZTYQIP-UHFFFAOYSA-N 2-[5-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-1,3,4-oxadiazol-2-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1=NN=C(O1)CC(=O)N1CC2=C(CC1)NN=N2 YJLUBHOZZTYQIP-UHFFFAOYSA-N 0.000 description 1
- MMWNKXIFVYQOTK-UHFFFAOYSA-N 2-bromopyridine-3-carboxylic acid Chemical compound OC(=O)C1=CC=CN=C1Br MMWNKXIFVYQOTK-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- AVXWWBFBRTXBRM-UHFFFAOYSA-N 3-bromopyridine-4-carboxylic acid Chemical compound OC(=O)C1=CC=NC=C1Br AVXWWBFBRTXBRM-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- 125000004070 6 membered heterocyclic group Chemical group 0.000 description 1
- YTYIMDRWPTUAHP-UHFFFAOYSA-N 6-Chloroindole Chemical compound ClC1=CC=C2C=CNC2=C1 YTYIMDRWPTUAHP-UHFFFAOYSA-N 0.000 description 1
- CONKBQPVFMXDOV-QHCPKHFHSA-N 6-[(5S)-5-[[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]methyl]-2-oxo-1,3-oxazolidin-3-yl]-3H-1,3-benzoxazol-2-one Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C[C@H]1CN(C(O1)=O)C1=CC2=C(NC(O2)=O)C=C1 CONKBQPVFMXDOV-QHCPKHFHSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 238000009010 Bradford assay Methods 0.000 description 1
- 0 C*C(C=C)=C(C(CC1)(CCN1C(c1c(*)[n](*)c2c1c(*)c(*)c(*)c2*)=O)[U]C)*=**=C=C Chemical compound C*C(C=C)=C(C(CC1)(CCN1C(c1c(*)[n](*)c2c1c(*)c(*)c(*)c2*)=O)[U]C)*=**=C=C 0.000 description 1
- 108091026890 Coding region Proteins 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 1
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- 239000007821 HATU Substances 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 206010062767 Hypophysitis Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 238000000023 Kugelrohr distillation Methods 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 1
- 238000007126 N-alkylation reaction Methods 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 108091034117 Oligonucleotide Proteins 0.000 description 1
- 206010030302 Oliguria Diseases 0.000 description 1
- BPQQTUXANYXVAA-UHFFFAOYSA-N Orthosilicate Chemical compound [O-][Si]([O-])([O-])[O-] BPQQTUXANYXVAA-UHFFFAOYSA-N 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 229910000831 Steel Inorganic materials 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 239000012317 TBTU Substances 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 206010047139 Vasoconstriction Diseases 0.000 description 1
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 230000002686 anti-diuretic effect Effects 0.000 description 1
- 230000000692 anti-sense effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 239000000074 antisense oligonucleotide Substances 0.000 description 1
- 238000012230 antisense oligonucleotides Methods 0.000 description 1
- 230000007529 anxiety like behavior Effects 0.000 description 1
- 230000010397 anxiety-related behavior Effects 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 238000010537 deprotonation reaction Methods 0.000 description 1
- CDHICTNQMQYRSM-UHFFFAOYSA-N di(propan-2-yl)alumane Chemical compound CC(C)[AlH]C(C)C CDHICTNQMQYRSM-UHFFFAOYSA-N 0.000 description 1
- 235000013681 dietary sucrose Nutrition 0.000 description 1
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 230000003828 downregulation Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229960001031 glucose Drugs 0.000 description 1
- 230000004116 glycogenolysis Effects 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 230000000004 hemodynamic effect Effects 0.000 description 1
- 125000004366 heterocycloalkenyl group Chemical group 0.000 description 1
- 210000001320 hippocampus Anatomy 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 description 1
- 210000003016 hypothalamus Anatomy 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000008011 inorganic excipient Substances 0.000 description 1
- 229960004903 invert sugar Drugs 0.000 description 1
- OCVXZQOKBHXGRU-UHFFFAOYSA-N iodine(1+) Chemical compound [I+] OCVXZQOKBHXGRU-UHFFFAOYSA-N 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 230000002197 limbic effect Effects 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 230000000873 masking effect Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000002107 myocardial effect Effects 0.000 description 1
- VSPPONOIKZXUBJ-UHFFFAOYSA-N n,n-diethylethanamine;oxolane Chemical compound C1CCOC1.CCN(CC)CC VSPPONOIKZXUBJ-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000011224 negative regulation of urine volume Effects 0.000 description 1
- 239000000712 neurohormone Substances 0.000 description 1
- 102000008434 neuropeptide hormone activity proteins Human genes 0.000 description 1
- 108040002669 neuropeptide hormone activity proteins Proteins 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 229940046166 oligodeoxynucleotide Drugs 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000008012 organic excipient Substances 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- WXHIJDCHNDBCNY-UHFFFAOYSA-N palladium dihydride Chemical compound [PdH2] WXHIJDCHNDBCNY-UHFFFAOYSA-N 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 210000002963 paraventricular hypothalamic nucleus Anatomy 0.000 description 1
- 125000000538 pentafluorophenyl group Chemical group FC1=C(F)C(F)=C(*)C(F)=C1F 0.000 description 1
- 125000002409 penten-3-yl group Chemical group C=CC(CC)* 0.000 description 1
- 125000002262 penten-4-yl group Chemical group C=CCC(C)* 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 210000003635 pituitary gland Anatomy 0.000 description 1
- LJCNRYVRMXRIQR-OLXYHTOASA-L potassium sodium L-tartrate Chemical compound [Na+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O LJCNRYVRMXRIQR-OLXYHTOASA-L 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000003757 reverse transcription PCR Methods 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000012163 sequencing technique Methods 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 239000001476 sodium potassium tartrate Substances 0.000 description 1
- 235000011006 sodium potassium tartrate Nutrition 0.000 description 1
- 210000001679 solitary nucleus Anatomy 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- LXMSZDCAJNLERA-ZHYRCANASA-N spironolactone Chemical class C([C@@H]1[C@]2(C)CC[C@@H]3[C@@]4(C)CCC(=O)C=C4C[C@H]([C@@H]13)SC(=O)C)C[C@@]21CCC(=O)O1 LXMSZDCAJNLERA-ZHYRCANASA-N 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000010959 steel Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000009182 swimming Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- HNCVRGCNKZVUSU-VIFPVBQESA-N tert-butyl (2s)-2-(methylsulfonyloxymethyl)pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC[C@H]1COS(C)(=O)=O HNCVRGCNKZVUSU-VIFPVBQESA-N 0.000 description 1
- 210000001550 testis Anatomy 0.000 description 1
- 125000004001 thioalkyl group Chemical group 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 230000025033 vasoconstriction Effects 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- VWQVUPCCIRVNHF-UHFFFAOYSA-N yttrium atom Chemical compound [Y] VWQVUPCCIRVNHF-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
- C07D491/20—Spiro-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Biomedical Technology (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- Pain & Pain Management (AREA)
- Psychiatry (AREA)
- Gastroenterology & Hepatology (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP06127334.8 | 2006-12-29 | ||
| EP06127334 | 2006-12-29 | ||
| PCT/EP2007/064183 WO2008080844A1 (fr) | 2006-12-29 | 2007-12-19 | Dérivés azaspiro |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2674154A1 true CA2674154A1 (fr) | 2008-07-10 |
Family
ID=39201403
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002674154A Abandoned CA2674154A1 (fr) | 2006-12-29 | 2007-12-19 | Derives azaspiro |
Country Status (22)
| Country | Link |
|---|---|
| US (3) | US8034937B2 (fr) |
| EP (1) | EP2125827B1 (fr) |
| JP (1) | JP2010514727A (fr) |
| KR (1) | KR101129861B1 (fr) |
| CN (1) | CN101589046B (fr) |
| AR (1) | AR064547A1 (fr) |
| AT (1) | ATE486877T1 (fr) |
| AU (1) | AU2007341379B2 (fr) |
| BR (1) | BRPI0720827A2 (fr) |
| CA (1) | CA2674154A1 (fr) |
| CL (1) | CL2007003832A1 (fr) |
| DE (1) | DE602007010359D1 (fr) |
| DK (1) | DK2125827T3 (fr) |
| ES (1) | ES2351949T3 (fr) |
| MX (1) | MX2009006921A (fr) |
| NO (1) | NO20092342L (fr) |
| PE (1) | PE20081844A1 (fr) |
| PL (1) | PL2125827T3 (fr) |
| PT (1) | PT2125827E (fr) |
| RU (1) | RU2009124419A (fr) |
| TW (1) | TW200835483A (fr) |
| WO (1) | WO2008080844A1 (fr) |
Families Citing this family (20)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BRPI0720004A2 (pt) * | 2006-12-07 | 2013-12-17 | Hoffmann La Roche | Derivados de espiro-piperidina como antagonista de receptor v1a |
| RU2009123133A (ru) * | 2006-12-22 | 2011-01-27 | Ф.Хоффманн-Ля Рош Аг (Ch) | Производные спиро-пиперидина |
| PL2448938T3 (pl) | 2009-06-29 | 2014-11-28 | Incyte Holdings Corp | Pirymidynony jako inhibitory PI3K |
| AR078948A1 (es) * | 2009-11-30 | 2011-12-14 | Lilly Co Eli | Compuestos de espiropiperidina, composicion farmaceutica que lo comprenden y su uso para preparar un medicamento util para tratar la diabetes |
| US8759359B2 (en) * | 2009-12-18 | 2014-06-24 | Incyte Corporation | Substituted heteroaryl fused derivatives as PI3K inhibitors |
| WO2011075630A1 (fr) * | 2009-12-18 | 2011-06-23 | Incyte Corporation | Dérivés substitués d'aryles et d'hétéroaryles fusionnés au titre d'inhibiteurs de pi3k |
| WO2011130342A1 (fr) | 2010-04-14 | 2011-10-20 | Incyte Corporation | Dérivés condensés en tant qu'inhibiteurs de ρi3κδ |
| US9062055B2 (en) | 2010-06-21 | 2015-06-23 | Incyte Corporation | Fused pyrrole derivatives as PI3K inhibitors |
| JP5961187B2 (ja) | 2010-12-20 | 2016-08-02 | インサイト・ホールディングス・コーポレイションＩｎｃｙｔｅ Ｈｏｌｄｉｎｇｓ Ｃｏｒｐｏｒａｔｉｏｎ | Ｐｉ３ｋ阻害剤としてのｎ−（１−（置換フェニル）エチル）−９ｈ−プリン−６−アミン |
| US9108984B2 (en) | 2011-03-14 | 2015-08-18 | Incyte Corporation | Substituted diamino-pyrimidine and diamino-pyridine derivatives as PI3K inhibitors |
| US9126948B2 (en) | 2011-03-25 | 2015-09-08 | Incyte Holdings Corporation | Pyrimidine-4,6-diamine derivatives as PI3K inhibitors |
| ES2464598T3 (es) | 2011-07-22 | 2014-06-03 | Université Joseph Fourier | Nuevos derivados bis-indólicos, procedimiento para su preparación, y sus utilizaciones como fármaco |
| HUE030869T2 (en) | 2011-09-02 | 2017-06-28 | Incyte Holdings Corp | Heterocyclic amines as inhibitors of PI3K |
| CN102568615B (zh) * | 2011-12-13 | 2013-05-22 | 华中科技大学 | 一种小型精密调平装置 |
| AR090548A1 (es) | 2012-04-02 | 2014-11-19 | Incyte Corp | Azaheterociclobencilaminas biciclicas como inhibidores de pi3k |
| WO2015191677A1 (fr) | 2014-06-11 | 2015-12-17 | Incyte Corporation | Dérivés d'hétéroarylaminoalkylphényle bicycliques à titre d'inhibiteurs de pi3k |
| AU2016222556B2 (en) | 2015-02-27 | 2020-08-27 | Incyte Holdings Corporation | Salts of Pl3K inhibitor and processes for their preparation |
| WO2016183063A1 (fr) | 2015-05-11 | 2016-11-17 | Incyte Corporation | Formes cristallines d'un inhibiteur de pi3k |
| WO2016183060A1 (fr) | 2015-05-11 | 2016-11-17 | Incyte Corporation | Procédé de synthèse d'un inhibiteur de phospho-inositide 3-kinases |
| US20230060003A1 (en) | 2019-10-29 | 2023-02-23 | Biogen Ma Inc. | Spirocyclic o-glycoprotein-2-acetamido-2-deoxy-3-d-glucopyranosidase inhibitors |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2761992B1 (fr) * | 1997-04-09 | 1999-06-11 | Hoechst Marion Roussel Inc | Nouveaux steroides 4-halogenes, leur procede et intermediaires de preparation, leur application comme medicaments et les compositions pharmaceutiques les renfermant |
| TWI279402B (en) * | 1999-08-20 | 2007-04-21 | Banyu Pharma Co Ltd | Spiro compounds having NPY antagonistic activities and agents containing the same |
| GB0003397D0 (en) | 2000-02-14 | 2000-04-05 | Merck Sharp & Dohme | Therapeutic agents |
| EP1701959A1 (fr) * | 2003-12-22 | 2006-09-20 | Pfizer Limited | Dérivés de triazole comme antagonistes de vasopréssine |
| GB0400700D0 (en) * | 2004-01-13 | 2004-02-18 | Pfizer Ltd | Compounds useful in therapy |
| GB0504556D0 (en) * | 2005-03-04 | 2005-04-13 | Pfizer Ltd | Novel pharmaceuticals |
-
2007
- 2007-12-19 CN CN2007800479989A patent/CN101589046B/zh not_active Expired - Fee Related
- 2007-12-19 PL PL07857806T patent/PL2125827T3/pl unknown
- 2007-12-19 AU AU2007341379A patent/AU2007341379B2/en not_active Expired - Fee Related
- 2007-12-19 DE DE602007010359T patent/DE602007010359D1/de active Active
- 2007-12-19 DK DK07857806.9T patent/DK2125827T3/da active
- 2007-12-19 PT PT07857806T patent/PT2125827E/pt unknown
- 2007-12-19 CA CA002674154A patent/CA2674154A1/fr not_active Abandoned
- 2007-12-19 EP EP07857806A patent/EP2125827B1/fr not_active Not-in-force
- 2007-12-19 BR BRPI0720827-8A patent/BRPI0720827A2/pt not_active IP Right Cessation
- 2007-12-19 JP JP2009543443A patent/JP2010514727A/ja active Pending
- 2007-12-19 KR KR1020097015840A patent/KR101129861B1/ko not_active IP Right Cessation
- 2007-12-19 WO PCT/EP2007/064183 patent/WO2008080844A1/fr active Application Filing
- 2007-12-19 AT AT07857806T patent/ATE486877T1/de active
- 2007-12-19 RU RU2009124419/04A patent/RU2009124419A/ru not_active Application Discontinuation
- 2007-12-19 ES ES07857806T patent/ES2351949T3/es active Active
- 2007-12-19 MX MX2009006921A patent/MX2009006921A/es active IP Right Grant
- 2007-12-20 US US11/960,779 patent/US8034937B2/en not_active Expired - Fee Related
- 2007-12-20 US US11/960,799 patent/US8044202B2/en not_active Expired - Fee Related
- 2007-12-20 US US11/960,823 patent/US8039624B2/en not_active Expired - Fee Related
- 2007-12-26 TW TW096150410A patent/TW200835483A/zh unknown
- 2007-12-27 AR ARP070105915A patent/AR064547A1/es not_active Application Discontinuation
- 2007-12-27 CL CL200703832A patent/CL2007003832A1/es unknown
-
2008
- 2008-01-02 PE PE2008000047A patent/PE20081844A1/es not_active Application Discontinuation
-
2009
- 2009-06-18 NO NO20092342A patent/NO20092342L/no not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| PL2125827T3 (pl) | 2011-04-29 |
| DE602007010359D1 (de) | 2010-12-16 |
| RU2009124419A (ru) | 2011-02-10 |
| US20080281103A1 (en) | 2008-11-13 |
| KR101129861B1 (ko) | 2012-04-24 |
| WO2008080844A9 (fr) | 2009-10-08 |
| PE20081844A1 (es) | 2009-01-26 |
| DK2125827T3 (da) | 2010-12-20 |
| US8039624B2 (en) | 2011-10-18 |
| AU2007341379A1 (en) | 2008-07-10 |
| CN101589046B (zh) | 2011-09-21 |
| CN101589046A (zh) | 2009-11-25 |
| US8044202B2 (en) | 2011-10-25 |
| JP2010514727A (ja) | 2010-05-06 |
| US20080161333A1 (en) | 2008-07-03 |
| US20080161332A1 (en) | 2008-07-03 |
| EP2125827A1 (fr) | 2009-12-02 |
| WO2008080844A1 (fr) | 2008-07-10 |
| NO20092342L (no) | 2009-07-02 |
| CL2007003832A1 (es) | 2008-07-25 |
| ATE486877T1 (de) | 2010-11-15 |
| KR20090094172A (ko) | 2009-09-03 |
| EP2125827B1 (fr) | 2010-11-03 |
| ES2351949T3 (es) | 2011-02-14 |
| BRPI0720827A2 (pt) | 2014-03-04 |
| AU2007341379B2 (en) | 2012-05-24 |
| PT2125827E (pt) | 2010-11-22 |
| MX2009006921A (es) | 2009-07-06 |
| US8034937B2 (en) | 2011-10-11 |
| TW200835483A (en) | 2008-09-01 |
| AR064547A1 (es) | 2009-04-08 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU2007341379B2 (en) | Azaspiro derivatives | |
| AU2006334423B2 (en) | Indol-3-yl-carbonyl-spiro-piperidine derivatives | |
| CA2615726C (fr) | Derives d'indol-3-yl-carbonyl-spiro-piperidine en tant qu'antagonistes du recepteur v1a | |
| EP2104677B1 (fr) | Dérivés de spiropipéridine glycinamide | |
| AU2007329066A1 (en) | Spiro-piperidine derivatives | |
| AU2006298828B2 (en) | Indol-3-yl-carbonyl-azaspiro derivatives as vasopressin receptor antagonists | |
| AU2007328994B2 (en) | Indoles which act as V1a receptor antagonists | |
| AU2007328995B2 (en) | Spiro-piperidine derivatives as VIa receptor antagonists | |
| CA2674518A1 (fr) | Derives de spiropiperidine | |
| AU2007341377B2 (en) | Indoles |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |
Effective date: 20131219 |